This invention relates to new bleomycin group antibiotics.
Bleomycins are antitumor antibiotics discovered by Umezawa et al., which are produced by an Actinomycete, Streptomyces verticillus [Umezawa et al., Journal of Antibiotics, 19A, p. 200 (1966)], and have structures represented by the formula [I] ##STR2## wherein R represents a terminal amine moiety of bleomycins.
A mixture comprising bleomycins A.sub.2 and B.sub.2 as major constituents is currently exhibiting an excellent effect in the chemotherapy of cancers, chiefly squamous cell carcinomas, particularly in the field of head and neck cancer, skin cancer, penis cancer, uterine cervix cancer, esophageal cancer, lung cancer, and malignant lymphoma.
When subjected to the action of an inactivating enzyme, however, conventional bleomycins are inactivated through the hydrolysis of a portion of their structure represented by the partial structural formula ##STR3## as shown by the following scheme: ##STR4## This fact was demonstrated by employing animal organs such as mouse liver. It was also found that bleomycins are comparatively resistant to inactivation in skin and lung where they act very actively, whereas easily subjected to inactivation in stomach and other organs where they do not act. It was further found that the inactivation action is weaker in the squamous cell carcinoma in mice than in the sarcoma in mice, both of which are induced by 20-methylcholanthrene [Umezawa et al., Journal of Antibiotics, 25, p. 409 (1972); Umezawa et al., Journal of Antibiotics, 27 p. 419 (1974)].
Moreover, it was found that the bleomycin-inactivating action is shown by squamous cell carcinoma in human head and neck resions, particularly markedly by those of the low differentiation type which are reported to be treated relatively ineffectively by bleomicins [Mueller et al., Cancer, 40, p. 2787 (1977)]. This is one of the reasons for the required improvement in bleomycins.
Consequently, the present inventors conducted extensive studies on the bleomycin group antibiotics which would be highly resistant to inactivating enzymes, and, as a result, found that a bleomycin antibiotics group having the partial structural formula ##STR5## (hereinafter such a group of bleomycins is referred to as N-methyl derivatives) is completely insusceptible to the action of inactivating enzymes. This finding has led to the accomplishment of this invention.